Project 1: Reduction of Pro-Inflammatory Signaling

Project Summary – Project 1 Convulsant chemical threat agents, such as the organophosphates (OPs) diisopropylfluorophosphate (DFP) and soman, can trigger seizures that progress to life-threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including spontaneous recurrent seizures (SRS) and mild-to-severe memory loss. Current medical countermeasures fail to sufficiently protect against these long-term neurological deficits. Project 1 will use a well-established rat model of acute DFP intoxication to test the hypothesis that therapies that promote resolution of inflammation when administered as adjuncts to standard of care will mitigate the long-term, adverse neurological consequences of acute OP intoxication. The scientific premise for this hypothesis includes experimental evidence that: (1) acute OP intoxication triggers a robust neuroinflammatory response in multiple brain regions that persists for up to 6 months; and (2) pro-inflammatory signaling is causally linked to epileptogenesis and cognitive dysfunction in non-OP models. We will focus our initial efforts on lipid mediators of inflammation. Our analyses of the brain lipidome in rats acutely intoxicated with DFP suggests two potential therapeutic approaches: inhibiting cyclooxygenase-2 (COX-2) to block the formation of prostaglandins, and inhibiting the enzyme soluble epoxide hydrolase (sEH) to stabilize anti-inflammatory lipid mediators. A small molecule inhibitor of sEH (sEHI) developed at UC Davis has been shown to significantly attenuate SRS in preclinical models of pilocarpine-induced epilepsy, improve cognitive function in preclinical models of Alzheimer’s disease (AD), and reduce pathology in models of AD, stroke and Parkinson’s disease. Our preliminary data suggest that sEHI also mitigates neuroinflammation and terminates SRS in the rat DFP model. Our goals are to: (1) Characterize the spatiotemporal profile of neuroinflammation in male and female rats following acute DFP intoxication in order to identify therapeutic targets, determine therapeutic windows, and develop translatable biomarkers of inflammation that predict SRS and/or cognitive dysfunction. (2) Evaluate the neuroprotective efficacy of sEHI and other compounds that target dysregulated inflammatory mediators in male and female rats acutely intoxicated with DFP. (3) Determine the safety of therapeutic lead(s) and their efficacy in protecting against adverse neurological consequences in a rat model of acute soman intoxication. If successful, Project 1 will identify novel therapeutic lead(s) that improve long-term neurological outcomes when used as adjuncts to standard of care, as well as biomarkers that identify individuals at increased risk for developing SRS and/or cognitive deficits following acute OP intoxication.